6-fluoro steroids and intermediates therefor



United States Patent 2,916,486 6-FLUOR0 STEROIDS AND INTERMEDIATESTHEREFOR John C. Babcock, Portage Township, Kalamazoo County, and JAllan Campbell and John A. Hogg, Kalamazoo Township, Kalamazoo County,Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporationof Michigan No Drawing. Application June 9, 1958 Serial No. 740,553 14Claims. (Cl. 260-43955) This invention relates to6-fluoro-17a-hydroxyprogesterone and 17 -acylates thereof andintermediates therefor. It relates more particularly to the novelcompounds 5,6- oxido-3fl,17a-dihydroxypregnan 20 one 3,17-diacylate,5,6-oxido-3B,17a-dihydroxypregnan 20 one 17-acylate, 6/3-fluoro3[3,5ot,l7oc trihydroxypregnan 20 one 3,17- diacylate,6fi-fluoro-3B,5a,17a-trihydroxypregnan-20-one 17-acylate and processesfor the production thereof. These novel compounds are useful asintermediates in the production of the physiologically active6a-fiu0l'0- 17a-hydroxyprogesterone and the 17-acylates thereof. Thisinvention is a continuation-in-part of our copending application SerialNo. 699,452, filed November 29, 1957, now Patent No. 2,838,496 issuedJune 10, 1958.

The new compounds and the process of the present invention areillustratively represented by the following formulae:

wherein R is hydrogen or R, and R is the acyl radical of an organiccarboxylic acid, preferably a hydrocarbon carboxylic acid containingfrom one to twelve carbon atoms, inclusive.

As used in this application, the Roman numeral following the name of acompound (or compounds) indicates the relation of the compound (orcompounds) to the reaction scheme depicted above.

The processes illustrated above comprise reacting a17a-hydroxypregnenolone 3,17-diacylate (I) dissolved in an inert organicsolvent such as chloroform, methylene chloride, methylene dichloride,carbon tetrachloride, benzene or the like, with an organic peracid suchas performic, peracetic, perbenzoic or other organic peracids. Thereaction is generally carried out at low temperatures such as betweenminus ten and plus ten degrees centigrade. However, higher or lowertemperatures, e.g., minus thirty to up to plus forty degrees centigradeare operable.

In the preferred embodiment of the invention temperatures between zeroand plus five degrees, a chlorinated hydrocarbon such as chloroform ormethylene dichloride and peracetic, perphthalic or perbenzoic acid areused. The peracid is usually used in a quantity from ten to twentypercent above to five times the amount theoretically required. At theend of the reaction, the mixture is neutralized, preferably with dilutesodium hydroxide, sodium or potassium carbonate or bicarbonate solution,washed with water and the thus produced mixture of5a,6a-oxido-3/3,l7a-dihydroxypregnan 20 one 3,17-diacylate (II) and thecorresponding 55,6;8-epimer recovered by evaporation of the solvents.When paracetic acid is used to form the 5,6-oxido compounds there ispreferably added to the reaction mixture a dry alkali metal acrylate,for example, sodium acetate.

Chromatography of the mixture followed by recrystallization from organicsolvents such as methanol, ethanol, Skellysolve B hexanes, heptanes,benzene, toluene, methylene chloride ether or the like, provides 5a,6ot-oxido- 3,3,17a-dihydroxypregnan-ZO-one 3,17-diacylate (II) and itsepimer 5 8,6fi-oxido-3fl,17ot-dihydroxypregnan-20-one 3,17-diacylate(II).

The thus obtained 5a,6a-oxido-3p,17a-dihydroxypregnan-20-one3,17-diacylate, dissolved in a suitable organic solvent, is reacted withhydrogen fluoride to give 6fl-fluoro-3 [3,511,l7u-trihydroxypregnan 20one 3,17-diacylate (III). The hydrogen fluoride can be gaseous hydrogenfluoride, hydrofluoric acid in aqueous solution, e.g., in 48 percentstrength, or a metal fluoride releasing hydrogen fluoride when treatedby an acid as, for instance, potassium or sodium bifluoride and an acidsuch as acetic, propionic or mineral acids such as perchloric, sulfuricacid or the like.

The reaction can be performed at between about minus seventy and plusfifty degrees centigrade. If anhydrous hydrogen fluoride is used,usually low temperatures, e.g., temperatures between minus seventy andplus ten degrees, are preferred. The hydrogen fluoride, for example, canbe allowed to enter from a hydrogen fluoride gas cylinder into a vesselnot reactive toward hydrogen fluoride. If aqueous hydrogen fluoride isused the reaction can be carried out between zero degrees and roomtemperature. Similarly, when the hydrogen fluoride is produced in situby the reaction of a metallic fluoride such as potassium bifluoride andan acid, reaction temperatures between zero to room temperature and evenhigher up to ninety degrees centigrade are useful. At low temperatures,solvents such as chloroform, methylene chloride, and particularly,tetrahydrofuran are used. In the reaction of the epoxide with potassiumbifluoride and an acid, organic acids are preferred such as acetic acid,propionic acid, formic acid or the like. However, other solvents such asneopentyl alcohol, isopropanol and the like with mineral acids such assulfuric acid, perchloric acid or the like can be used.

The reaction period is usually between fifteen minutes and four hours,with reaction times of approximately two to three hours usually beingsuflicient for anhydrous hydrogen fluoride. When potassium bifluoride isused, reaction periods of twelve hours to five days are employed. Afterthe reaction is terminated the material is isolated by methods wellknown in the art, e.g., neutralizing the excess hydrogen fluoride with abase, e.g., sodium carbonate, potassium bicarbonate, sodium hydroxide,or the like, and extracting the product with waterimmiscible solventssuch as methylene chloride, chloroform, benzene, ether, hexanes and thelike. Evaporation of the organic solvents gives the crude material,which is purified generally by recrystallization from organic solventssuch as methanol, ethanol, acetone, Skellysolve B hexane, benzene,methylene chloride or the like, to give pure6/3-fluoro-3p,5a,l7a-trihydroxypregnan-20-one 3,17- diacylate.

Crude, or purified 6fi-fiuoro-3fi,5a,17wtrihydroxypregnan-20-one3,17-diacylate (III) is hydrolyzed in a watermiscible solvent,preferably in an aqueous or acetone acidic medium. As solvent alkanols,methanol and and ethanol are the preferred alkanols; however, othersuitable water-miscible solvents such as tertiary butyl alcohol, propylalcohol, isopropyl alcohol, dioxane, acetone, acetic acid or the likecan be used.

The hydrolysis of 6/3-fluoro-3}3,5a,l7a-trihydroxypregnan-ZO-one3,17-diacylate is productive of 6fi-fiuoro-3B,5a,17a-trihydroxypregnan-20-one 17-acylate (III); and subsequentoxidation thereof with sodium dichromate in acetic acid yields6fi-fluoro-5a,l7u-dihydroxypregnane- 3,20-dione 17-acylate (IV). Thecrude product can be purified using known methods, for example, byrecrystallization from organic solvents such as acetone, ethyl acetate,Skellysolve B hexanes, methanol, tertiary butyl alcohol, ether, or thelike, or mixture thereof to give pure 65-fiuoro 5a,17u dihydroxypregnane3,20 dione 17- acylate.

The thus obtained 6B-fiuoro-5a,17u-dihydroxypregnane- 3,20-dione17-acylate is thereupon chemically dehydrated. Dehydration can beeffected in alkali solution or in acidic solution. In the preferredembodiment of the present invention, acid dehydration is used. Thecompound (IV) is dissolved or suspended in solvents unreactive to theacid employed, e.g., methylene chloride, chloroform, dioxane, carbontetrachloride and the like, and the selected acid is added to thesolution or suspension. Acids particularly useful for this reaction arestrong acids, e.g., gaseous hydrogen chloride or hydrogen bromide,sulfuric acid and the like, with gaseous hydrogen chloride preferred.For dehydration with alkali compound IV is dissolved in methanol,ethanol, dioxane, or other convenient solvents, unreactive to the baseemployed. The solution is purged of oxygen by bubbling nitrogen throughthe solution and then allowed to react with an oxygen-free alkali metalbase solution. Sodium or potassium hydroxide are the preferred bases.However, alkali metal alkoxides, barium hydroxide, calcium hydroxide, orthe like, can be used.

Depending on the amount of acid or base used, the 6ozand 6/8-isomers areobtained. The dehydration produces at first the 6,8-isomer, which, beingless stable in strong acid or bases, rearranges to the 6a-isomer. If, atthe start of the dehydration reaction the medium is strongly acidic,only 6u-fluoro-17m-hydroxyprogesterone l7-acylate is obtained. A weaklyacidic or basic medium furnishes the 6B-fluoro-17a-hydroxyprogesterone17-acylate, while a strongly basic medium furnishes the free alcohol asthe a-epimer, i.e. 6a-fluoro-l7a-hydroxyprogesterone. The 6,B-isomer cansubsequently be converted to the 6a-isomer by treatment with strong acidor base.

The thus obtained 6-fiuoro-17ot-hydroxyprogesterone 17-acylates or thefree alcohol, 6-fiuoro-l7a-hydroxyprogesterone, obtained when moreconcentrated solution of strong base is used in the dehydration step,can be isolated respectively from the reaction mixture and purified byconventional procedures. Such procedures include diluting with water andeither recovering by filtration or by extracting the mixture with awater-immiscible solvent, for example, methylene chloride, chloroform,hexanes, benzene, ether and the like, and then evaporating the solvent.The thus obtained solids are purified by conventional procedures, suchas recrystallization from organic solvent, such as methanol, ethanol,Skellysolve B hexanes, ethyl acetate, benzene or the like to obtain thepure 6-fluoro-17a-hydroxyprogesterone or the l7-acylate thereof,respectively.

In the preferred embodiment of this invention 6-fluoro-17u-hydroxyprogesterone (VI) is prepared from6-fiuorol7u-hydroxyprogesterone 17-acylate in a separate step bysaponification. For this purpose the 6-fiuoro-17a-hydroxyprogesteronel7-acylate is allowed to react with an alkali metal hydroxide such assodium hydroxide, potassium hydroxide or a carbonate such as sodium orpotassium carbonate, bicarbonate or the like or with an alkali earthmetal hydroxide such as barium or calcium hydroxide in alcoholicsolution at room temperature for a reaction time of from one to 24 hoursto obtain the 6-fluoro-17a-hydroxyprogesterone. To isolate the productfrom the reaction mixture, the reaction mixture is first neutralizedwith aqueous acid such as aqueous acetic acid, aqueous hydrochloric orsulfuric acid and thereupon diluted with water and extracted with awater-immiscible organic solvent such as methylene chloride, chloroform,benzene, ether, or the like, and the extracts dried and evaporated togive the crude material. The crude material can then be recrystallizedfrom organic solvents such as methanol, ethanol, acetone, Skellysolve Bhexanes, ethyl acetate, methylene chloride or the like to give pure6-fluoro-l7a-hydroxyprogesterone. From the thus obtained6-fluoro-17a-hydroxyprogesterone, esters can be prepared byesterification carried out by methods well established in the art ofesterifying tertiary hydroxyl groups in the 17a-position of steroids ofthe pregnane series, e.g., Huang-Minlon et al., J. Am. Chem. Soc., 74,5394 (1952). Huang-Minlon et al. describe both a cold method and a hotmethod, both of which are equally useful in the esterification of6a-fiuoro-17a-hydroxyprogesterone. If in the esterification of the6B-isomer, the fi-isomers are desired, mild conditions are necessary(cold method, low amount of acid catalyst) since otherwise a conversionof the 6/3-isomer to the 6a-isomer takes place.

An alternate process of the present invention comprises: reacting al7ot-hydroxypregnenolone 17-acylate (I) in a suitable solvent (e.g.chloroform, methylene chloride, benzene) with an organic peracid, e.g.peracetic acid, perbenzoic acid, perphthalic acid and the like to obtain3,8,17a-dihydroxy-5a,6a-oxidopregnan-20-one l7- acylate (II); treatingthe thus produced 313,17a-dihydr0xy- 5a,6u-oxidopregnan-20-onel7-acylate with hydrogen fluoride to obtain35,50:17a-trihydroxy-6;8-fluoropregnan-20- one 17-acylate (III);oxidizing the thus produced 35.50:,17ot-trihydroxy-6B-fluoropregnan-20-one 17-acylate with sodiumdichromate in acetic acid to obtain5a,17a-dlhydroxy-6/3-fiuoropregnane-3,20-dione 17-acylate (IV); anddehydrating the thus obtained5a,l7a-dihydroxy-6flfluoropregnane-3,20-dione 17-acylate with a base; orpreferably, with an acid to obtain 6a-fiuoro-l7a-hydroxy-4-pregnene-3,20-dione 17-acylate (6a-fiuoro-l7a-hydroxyprogesterone17-acylate) (V); saponification of 6a-fluorol7a-hydroxyprogesteronel7-acylate to obtain 6a-fiuorol7a-hydroxyprogesterone (VI) is carriedout by allowing the l7-acylate (V) to react with a base, e.g., sodium orpotassium hydroxide, or for an extended period with an aqueous acid suchas dilute hydrochloric acid. When peracetic acid is used to form the5,6-oxido compound 'of a hydrocarbon carboxylic acid containing from oneto twelve carbon atoms, inclusive, in the presence ofparatoluene-sulfonic acid to produce a 17a-hydroxypregnenolone3,17-diacylate. Refiuxing the 17a-hydroxypregnenolone 3,17-diacylatewith concentrated strong mineral acid (e.g., hydrochloric acid) in a dryalcohol (e.g., ethanol or methanol) is productive of a17a-hydroxypregnenolone 17-acylate (I).

The preparation of the starting compounds of this invention areillustrated in Preparations 1A and 1B, which follow.

The following preparations and examples are illustrative of the productsand process of the present invention and are not to be construed aslimiting.

PREPARATION 1A l7a-hydroxypregnenolone 3,17-diacetate 400 milliliters ofacetic acid and 100 milliliters of acetic anhydride. The solution becameclear after about a thirty-minute period. After another two-hour periodthe reatcion mixture was poured into ice-water and the precipitatecollected, washed well with water and dried to yield 30.4 grams ofproduct with a melting point of 166-178 degrees centigrade.Recrystallization from a mixture of acetone and Skellysolve B (hexanehydrocarbons) yielded 24.2 grams of pure l7a-hydroxypregnenolone3,17-diacetate with a melting point of 179 to 181 degrees centigrade androtation [zxJ minus 65 degrees in chloroform.

In a manner corresponding to that of the foregoing preparation,17a-hydroxypregnenolone 3,17-dicaproate, 17a-hydroxypregnenolone3,17-diphenylacetate, 17a-hydroxypregnenolone 3,17-di(8-cyclopentylpropionate), 170chydroxypregnenolone 3,17-diacrylate,17a-hydroxypregnenolone 3,17-divalerate, 17a-hydroxypregnenolone 3,17-dfirimethylacetate, 17a-hydroxypregnenolone 3,17-di-t-bucarboxylate,17a-hydroxypregnenolone 3,17-diethylbutyrate, 17a-hydroxypregnenolone3,17-dicyclohexylacetate, 17x-hydroxypregnenolone 3,17-di-o-toluate,17u-hydroxypregnenolone 3,17-dimonoglutarate, 17u-hydroxypregnenolone3,17-dimonodiglycolate, 17a-hydr0xypregnenolone3,17-dimono-B-methylglutarate, 17a-hydroxypregnenolone3,17-dimono-5,13-dimethylglutarate, 17a-hydroxypregnenolone3,17-diethoxyacetate, 17a-hydroxypregnenolone 3,17- dilaurate,17a-hydroxypregnenolone 3,17-dibutyrate, 17ahydroxypregnenolone3,17-dipropionate, 17a-hydroxy pregnenolone 3,17-diisovalerate,l7u-hydroxypregnenolone 3,17-dienanthate and l7a-hydroxypregnenolone3,17- dicaprylatc are prepared by dissolving 17a-hydroxypregnenolone ina solution comprising a mixture of the appropriate acid and itsanhydride together with p-toluenesulfonic acid. The crude diester isisolated in accordance with the procedure of the foregoing preparation.If the corresponding acid or its anhydride is solid, an inert solventsuch as benzene, chloroform or dioxane can be added to effect solutionand to provide a liquid esterification reaction medium.

PREPARATION 1B 17u-hydroxypregnenolone 17-acetate 0.4 gram of17a-hydroxypregnenolone 3,17-diacetate in fifteen milliliters ofmethanol and 0.13 milliliter of concentrated hydrochloric acid wasrefluxed for one hour. About half of the methanol was evaporated under astream of nitrogen. 0.35 gram of product was flooded out with water,collected, dried and recrystallized from tylacetate,17a-hydroxypregnenolone 3,17-dicyclopentyl- .45

acetone to yield 17a-hydroxypregnenolone 17-acetate with a melting pointof 224 to 228 degrees centigrade and rotation [041 minus 69 degrees inchloroform.

Analysis.Calculated for C H O C, 73.76; H, 9.15. Found: C, 73.64; H,9.46.

In the same manner as in the foregoing preparation, substitution of oneof the 17a-hydroxypregneno1one 3,17- diacylates disclosed in Preparation1A as the starting steroid, is productive of the corresponding17a-hydroxypregnenolone 17-acylate.

EXAMPLE 1 5 ,6 -0xid0-3 3,1 7 a-dihydroxy pregnan-Z 0-0ne3,17-diacetates (II) A solution of twenty grams of17a-hydroxypregnenolone 3,17-diacetate and 2.5 grams of sodium acetatein 250 milliliters of chloroform was cooled to five degrees centigradeand 25 milliliters of forty percent peracetic acid added with stirring.After a period of three hours the solution was washed with water, dilutesodium hydroxide, again with water, dried, and the solvent removed. Theresidue resisted crystallization and was chromatographed through a 400gram column of Florisil, a synthetic magnesium silicate. The fl-oxidewas eluted with six percent acetone in Skellysolve B and recrystallizedfrom methanol to yield 3.17 grams of5a,6/3-0Xid0-3,B,17adihydroxypregnan-20-one 3,17-diacetate, with amelting point of 168 to 173 degrees centigrade and rotation [(11 minus45 degrees in chloroform.

Analysis.Calculated for C H O C, 69.41; H, 8.39. Found: C, 69.72; H,8.35.

The 55,6;8-oxido-3fl,17a-dihydroXypregnan-ZO-Qne 3,17- diacetate thusproduced possesses central nervous system regulating activity. Thea-oxide was eluted with six to ten percent acetone in Skellysolve B andrecrystallized from methanol to yield 8.0 grams of 5a,6oc-0XidO-33,l7adihydroxypregnan-ZO-one 3,17-diacetate with a melting point of 219to 223 degrees centigrade and rotation [od minus 61 degrees inchloroform.

Analysis.Calculated for C H O C, 69.41; H, 8.39. Found: C, 69.08; H,8.31.

In the same manner as in the foregoing example, reacting other3,17-diacylates of 17a-hydroxypregnenolone disclosed in Preparation 1Awith peracetic acid and sodium acetate is productive of thecorresponding 506,6OL-OXidO- 35,170: dihydroxy pregnan-20-one3,17-diacylates and 5fi,6;3 oxido 3fl,17 x dihydroxypregnan 20 one 3,17-diacylates.

EXAMPLE 2 5 ,6 0xid0-3;9,1 7a-dihydr0xypregnan-20-0ne 17-acetates Asolution of grams of crude 17a-hydroxypregnenolone 17-acetate (obtainedfrom Preparation 1B) dissolved in about six liters of benzene was cooledto fifteen degrees centigrade and seventeen grams of anhydrous sodiumacetate was added, followed by 170 milliliters of forty percentperacetic acid with stirring. The temperature of the reactants was keptat fifteen degrees centigrade for a period of about 2.25 hours, then thesolution was washed twice with water accompanied by very gentleswirling. Vigorous shaking during the third washing with water causedthe a-oxide (II) to precipitate. It was collected, washed with water andbenzene and dried to yield 95 grams with a melting point of 248 to 249degrees centigrade. Recrystallization from acetone gave pure 5a,6x-oxido-3fi,17a-dihydroxypregnan-20-one 17-acetate with a melting pointof 251 to 252 degrees centigrade and rotation [04 minus 71 degrees inchloroform.

Analysis-Calculated for C H O C, 70.74; H, 8.77. Found: C, 70.43; H,8.97.

An additional 24.7 grams of 5a,6oc0Xid03}3,17a-dihydroxy-pregnan-ZO-one17-acetate with a melting point of 238 to 244 degrees centigrade wasobtained from the benzene filtrate. 1

The mother liquor of the second crop after several days deposited largechunks along with smaller crystals. The chunks were hand separated andrecrystallized twice from benzene to yield 0.6 gram of 53,6B-oxido-3,B,17a-dihydroxy-pregnan-ZO-one 17-acetate with a meltingpoint of 227 to 229 degrees centigrade and rotation [(11 minus nineteendegrees in chloroform.

Analysis.--Calculated for C l-1 C, 70.74; H, 8.77. Found: C, 71.10; H,8.97.

5/3,6B-oxido-3B,17u-dihydroxypregnan-20-one 17-acetate possesses centralnervous system regulating activity.

In a manner similar to that of the foregoing example, substitution ofanother 17a-hydroxypregnenolone 17-acylate as the starting steroid isproductive of the corresponding5a,6a-oxido3fi,l7a-dihydroxypregnan-20-one 17-acylate and55,6;8-oxido-3B,17a-dihydroxypregnan-ZO-one 17-acylate. Representativecompounds thus prepared are 5,6 oxido 3,8,17a dihydroxypregnan 20 one17-caproate, 5,6-oxido-3/3,17wdihydrQXypregnan-ZO-one 17-phenylacetate,5,6-oxido-3 3,17a-dihydroxypregnan-20- one 17(B-cyclopentylpropionate),5,6-oxido-3t3, 17u-dihydroxypregnan-ZO-one 17-acrylate,5,6-oxido-3B,17a-dihydroxypregnan-ZO-one 17-valerate, 5,6-oxidodihydroxypregnan-ZO-one 17-trimethylacetate,5,6-oxido-3B,17a-dihydroxypregnan-ZO-one 17-(t-butylacetate), 5,6-oxido-35,17a-dihydroxypregnan-20-one l7-cyclopentylcarboxylate,5,6-oxido-3p,17a-dihydroxypregnan-20-one 17-ethylbutyrate, 5,6-oxido-38,17a-dihydroxypregnan-ZO-one 17- cyclohexylacetate, 5,6-oxido 35,1711dihydroxypregnan- 20-one 17-(o-toluate)5.6-oxido-35,17a-dihydroxypregnan-ZO-one 17-monoglutarate, 5,6 oxido36,1711 dihydroxypregnan-ZO-one 17 monodiglycolate, 5,6-oxido- 33,17wdihydroxypregnan-ZO-one 17-(mono-fl,fl-dimethylglutarate),5,6-oxido 3 3,17u-dihydroxypregnan-20-one l7-ethoxyacetate,5,6-oXido-3B,17a-dihydroxypregnan-20- one 17-laurate,5,6-oxido-3/8,17u-dihydroxypregnan-20-one 17-butyrate, 5 ,6-oxidodihydroxypregnan-20-one l7-propionate,5,6-oxido-3B,17a-dihydroxy-pregnan-20-one 17 valerate, 5,6 oxido 35,17adihydroxypregnan 20 one 17-enanthate,5,6-oxido-3l8,17u-dihydroxy-pregnan-20-one 17-caprylate and the like.

EXAMPLE 3 Ten milliliters of cooled methylene chloride was added to 1.5grams of hydrogen fluoride cooled in a Dry Iceacetone bath. 4.3 grams of5zx,6oc-0Xid0-3fi,17a-dihydroxypregnan-20-one 3,17-diacetate (II) intwenty milliliters of cooled methylene chloride was added to thehydrogen fluoride-methylene chloride. The resulting solution was allowedto stand at room temperature for four hours, then two milliliters ofpyridine was added. The methylene chloride was removed and Water added.The gummy insoluble material was separated and washed thoroughly withether to give clean crystals. This product was recrystallized fromacetone to yield 1.2 grams 6 8-fluoro-3B,5a,17a-trihydroxypregnan 20 one3,17-diacetate with a melting point of 253 degrees centigrade and anoptical rotation of [1x1 minus 33 degrees in chloroform.

AnaIysis.Calculated for C H FO C, 66.35; H, 8.25; F, 4.20. Found: C,66.14; H, 8.25; F, 4.15.

In the same manner as in the foregoing example, substituting as thestarting steroid one of the Saba-oxido- 3fl,17a dihydroxypregnan 20 one3,17 diacylates disclosed in Example 2 is productive of thecorresponding 6fi-fiuoro-3 13,5 (1,17 a-trihydroxypregnan-20-one 3,17-diacylate.

EXAMPLE 4 39 milliliters of precooled chloroform and 98 milliliters ofprecooled tetrahydrofuran were added with swirling to 53 grams ofhydrogen fluoride in a polyethylene bottle cooled in a Dry Ice-acetonebath. This solution was added to a solution (cooled in a Dry Ice-acetonebath) of 45 grams of 5a,6a-oxido-3B,l7a-dihydroxypregnan- 20-one17-acetate (II) in 200 milliliters of chloroform. After storing atfifteen degrees centigrade for 2.25 hours the reaction mixture waspoured into one liter of ice-water containing milliliters of pyridine.The upper aqueous phase was extracted twice with methylene chloride. Theextracts were combined with the lower chloroform phase and washed withdilute hydrochloric acid, water, dilute sodium carbonate and again withwater. Each aqueous phase was back extracted with the same methylenechloride solution and the combined extracts were dried over magnesiumsulfate, filtered and concentrated to dryness. the residue was a glassysolid.

From a similar run the product was obtained as a crystalline monohydrateby recrystallization from aqueous methanol to yield6B-fiuoro-3[3,5u,17a-trihydroxypregnan- 20-one 17-acetate with a meltingpoint of 224 to 228 degrees centigrade and an optical rotation [0:1 ofplus 21 degrees in chloroform.

Analysis.Calculated for C H FO -H O: C, 64.46; H, 8.70; F, 4.41. Found:C, 64.98; H, 8.91; F, 4.16.

In the same manner as in the foregoing example, substituting as thestarting compound one of the 50:, 6a-oxido- 3f,17a-dihydroxypregnan-ZO-one 17-acylates disclosed in Example 2 isproductive of the corresponding 6B-fluoro-3635a,17a-trihydroxypregnan-20-one 17-acylate.

EXAMPLE 5 6 a-flu0r0-3 {3,5 41,1 7a-trihydroxypregnan-ZO-one 1 7-aclate(Ill A solution of 1.2 grams of6/8-fluoro-3{3,5a,17a-trihydroxypregnan-ZO-one 3,17-diacetate (III),fifty milliliters of methanol and 0.5 milliliter of concentratedhydrochloric acid was refluxed for one hour. About half of the methanolwas evaporated under a stream of nitrogen. The product was flooded outwith water, collected, dried and crystallized from acetone to give 1.15grams of 6flfluoro 3]3,5oc,l7a trihydroxypregnan-ZO-one 17-acetate(III).

In the same manner as in the foregoing example, reacting other 63-fluoro-3fi,5a,17a-trihydroxypregnan-20- one 3,17-diacylates dissolvedin an alcohol with a strong mineral acid (e.g., concentratedhydrochloric) is productive of the corresponding6/3-fluoro-3B,5a,17a-trihydr0xypregnan-20-one 17-acylates.

EXAMPLE 6 6 B-fluoro-S 0a,] 7a-dihydr0xypregnan-3,20-di0ne 1 7 -acetateForty grams of 6;3-fluoro-3;8,5a,17oa-trihydroxypregnan- 20-one17-acetate (III) was dissolved in 500 milliliters of acetic acid and 45grams of sodium dichromate dihydrate in 450 milliliters of acetic acidwas immediately added to the steroid solution with swirling and coolingin a water bath for about five minutes. The reaction mixture was allowedto stand at room temperature for about 1.5 hours. The solution wascooled to fifteen degrees centigrade and the product filtered off andwashed twice with small portions of methanol. After drying the productweighed 34.7 grams and had a melting point of 246 to 250 degreescentigrade. Recrystallization from boiling methanol yielded6B-fiuoro-5a,17a-dihydroxypregnane 3,20 dione 17-acetate (IV) with amelting point of 265 to 267.5 degrees centigrade.

In the same manner as in the foregoing example, other65-fiuoro-3fi,5a,17a-trihydroxypregnan-20-one 17-acylates (III)disclosed in Example 5 when dissolved in acetic acid and oxidized withsodium dischromate dihydrate are productive of the corresponding6B-fiuoro-5a,17a-dihydroxypregnan-3,20-dione 17-acylates.

EXAMPLE 7 6a-flu0r0-17u-hydr0xypr0gesterone 17-acetate (V) A slurry often grams of 6B-fluoro-5a,17a-dihydroxypregnane-3,20-dione 17-acetate(IV) in 100 milliliters of chloroform and one milliliter of absoluteethanol was cooled to minus five degrees centigrade in an ice-salt bathand then saturated with hydrogen chloride. After four hours nitrogen wasbubbled through the reaction mixture, followed by washing twice withwater, once with sodium bicarbonate solution and again with water. Afterdrying and filtering, the solvent was removed and the residuerecrystallized from a mixture of acetone and Skellysolve B (hexanehydrocarbons). A yield of 6.1 grams of 6afluoro-l7a-hydroxyprogesterone17-acetate (V) was obtained with a melting point of 252 to 256 degreescentigrade (with decomposition). Recrystallization of a second crop ofthe product gave 0.7 gram having a melting point of 248 to 255 degreescentigrade.

In the same manner as in the foregoing example, reacting other6B-fiuoro-5u,17a-dihydroxypregnane-3,20- dione 17-acylates (IV) inchloroform solution with hydrogen chloride is productive of thecorresponding 6mfluoro-17a-hydroxyprogesterone 17-acylates (V).

EXAMPLE 8 6 a-fluoro-J 7a-hydr0xy progesterone (VI) A solution of 1.9grams of 6a-fiuoro-17a-hydroxyprogesterone 17-acetate (V) in fiftymilliliters of one percent sodium hydroxide in ninety percent methanoland twenty milliliters of methylene chloride was purged with nitrogen.After standing overnight at room temperature the solution was dilutedwith methylene chloride and washed three times with water. The aqueousphases were back extracted with methylene chloride. The extracts werecombined, dried and concentrated to about twenty milliliters and pouredonto a 150 gram chromatographic column of Florisil (synethetic magnesiumsilicate). After washing the column with increasing amounts of acetonein Skellysolve B, the product was eluted with two to eight percent ofacetone in 1:1 mixtures of Skellysolve B and methylene chloride.Recrystallization from a mixture of acetone and Skellysolve B yielded0.75 gram of 6a-fluoro- 17a-hydroxyprogesterone (V1) with a meltingpoint of 234 to 237 degrees centigrade,

Rig}, 236 my (ar 15,775) and an optical rotation [:1 plus 79 degrees inchloroform.

Analysis.Calculated for C H FO C, 72.38; H, 8.39; F, 5.45. Found: C,72.18; H, 8.59, F, 5.17.

Reacting other oa-fiuoro-17a-hydroxyprogesterone 17- acylates (V)disclosed in Example 7, in the same manner as in Example 8, is alsoproductive of 6oz-fiu0r0-17cchydroxyprogesterone (VI).

EXAMPLE 9 3- (N -pyrr0lidinyl -6-flu0r0-1 7a-hydr0xypragesterone17-acetate A mixture of 2.1 grams of 611- and6fi-fil10r0-17ahydroxyprogesterone 17-acetate (V) was dissolved in fiftymilliliters of methanol containing a little methylene chloride to aid indissolving the steroid. The solution was filtered to remove foreignparticles then concentrated to about 25 milliliters. Nitrogen wasbubbled through the solution and 1.5 milliliters of pyrrolidine wasadded. The solution was boiled for about three minutes then seeded. Theprecipitate was collected and washed with a small amount of coldmethanol to yield 1.0 gram of the 3-enamine of6-fluoro-17a-hydroxyprogesterone 17- acetate having a melting point of208 to 218 degrees centigrade (with decomposition), rotation [111 minus174 degrees in pyridine,

xggg 276 m,., (1 =19,150, x335 276 11..., a =23,725

Analysis-Calculated for C27H38FNO3Z C, 73.10; H, 8.63; F, 4.28; N, 3.16.Found: C, 73.11; H, 8.71; F, 3.98; N, 3.38.

It is to be understood that the invention is not to be limited to theexact details of operation or exact compounds shown and described, asobvious modifications and equivalents will be apparent to one skilled inthe art, and the invention is therefore to be limited only by the scopeof the appended claims.

We claim:

1. 6,3-fluoro-3B,5a,17a trihydroxypregnan-ZO-one 17- acylate, whereinthe acyl group is of a hydrocarbon carboxylic acid containing from oneto twelve carbon atoms, inclusive.

2. 6/3-fluoro-3/3,5u,17a trihydroxypregnan-ZO-one 17- acetate.

3. 6fl-fluoro-3fi,5u,17a-trihydroxypregnan-20-one 3,17- diacylate,wherein the acyl radical is of a hydrocarbon carboxylic acid containingfrom one to twelve carbon atoms, inclusive.

4. 6p-fluoro-3fi,5u,17u-trihydroxypregnan-20-one 3,17- diacetate.

5. 5,6-OXidO-3fi,17oc dihydroxypregnan-ZO-one 3,17- diacylate, whereinthe acyl group is of a hydrocarbon carboxylic acid containing from oneto twelve carbon atoms, inclusive.

6. 5a,6oc-OXidO-3I3,17oc dihydroxypregnan-ZO-one 3,17- diacylate,wherein the acyl group is of a hydrocarbon carboxylic acid containingfrom one to twelve carbon atoms, inclusive.

7. 5 3,6 3-0XidO-3fi,17oc dihydroxypregnan-ZO-one 3,17- diacylate,wherein the acyl group is of a hydrocarbon carboxylic acid containingfrom one to twelve carbon atoms, inclusive.

8. 5oz,6oz-0XidO-3fi,l7a dihydroxypregnan-ZO-one 3,17- diacetate.

9. 5/3,6,6'-oxido-3p,17a dihydroxypregnan-ZO-one 3,17- diacetate.

10. 5,6-oxido-3fi,17a-dihydroxypregnan 20 one 17- acylate, wherein theacyl group is of a hydrocarbon carboxylic acid containing from one totwelve carbon atoms, inclusive.

11. 5a,60z-OXidO-3}3,l7oc dihydroxypregnan-ZO-one 17- acylate, whereinthe acyl group is of a hydrocarbon carboxylic acid containing from oneto twelve carbon atoms, inclusive.

12. 5p,6/8-oxido-3B,17a dihydroxypregnan-ZO-one 17- acylate, wherein theacyl group is of a hydrocarbon carboxylic acid containing from one totwelve carbon atoms, inclusive.

13. 5oc,6a-OXidO-3 3,17ot dihydroxypregnan-ZO-one 17- acetate.

14. 5fi,6 8-oxido-3fl,17a dihydroxypregnan-ZO-one 17- acetate.

References Cited in the file of this patent UNITED STATES PATENTS2,838,496 Babcock et al. June 10, 1958

1. 6-BFLUORO-3B,5A,17A- TRIHYDROXYPREGNAN-20-ONE 17 ACYLATE, WHEREIN THEACYL GROUP IS OF A HYDROCARBON CARBOXYLIC ACID CONTAINING FROM ONE TOTWELVE CARBON ATOMS, INCLUSIVE.
 5. 5,6-OXIDE-3B,17A -DIHYDROXYPREGAN-20-ONE 3,17DIACYLATE, WHEREIN THE ACYL GROUP IF OFHYDROCARBON CARBOXYLIC ACID CONTAINING FROM ONE TO TWELVE CARBON ATOMS,INCLUSIVE.